Microfluidic analytical systems are being looked to more and more as a viable means for meeting to the desire to increase throughput, decrease costs, improve automation, and improve data quality in the analysis of chemical and biochemical systems. In many cases, the promise of microfluidics to accomplish many of these goals has been met through the massive parallelization of miniaturized conventional technologies. While providing many benefits over the conventional technologies, the simpler massively parallel systems result in only incremental improvements over conventional technologies, e.g., by a factor of the number of parallel channels. In particular, while removing some of the limitations of conventional technologies, these simpler microfluidic systems do not remove them all. Thus, these systems typically make a minor improvement over conventional systems, e.g., costs, only to run into a further limitation that the microfluidic system doesn""t solve, e.g., concurrent control of parallel systems.
Commonly owned Published International Application No. 98/00231 describes methods and systems that address some of these concerns. In particular, assay methods are described that screen test compounds, e.g., pharmaceutical library compounds, in series to determine whether any of these compounds have a desired effect on a given biological system. By screening the compounds in series in a single microfluidic channel network, control of the system is simplified, while still yielding the relatively high serial throughput. Additionally, the throughput is further increased when the system is parallelized, e.g., by providing multiple separate channel networks in which multiple compounds are serially screened.
In serialized systems, however, difficulties can arise in attempting to maximize throughput. In particular, optimizing throughput requires minimizing space between serially introduced compounds within the system. However, a number of factors, e.g., diffusion, electrophoretic biasing, dispersion of fluid materials, etc., weigh against the minimization of the space between adjacent serially introduced compounds. In particular, because fluid samples will diffuse, disperse, and be electrophoretically biased, or smeared, it has typically required that substantial space be given to each fluid volume, in order to avoid intermixing of fluid materials that are introduced in succession. The more space that is required between test compounds, the more time it will take to screen multiple compounds. Further, such dispersion can result in excessive dilution of fluid materials within microscale channels. Due to the extremely small dimensions of microfluidic systems, one generally begins a microfluidic analysis with substantially less material than in conventional analyses, one often cannot afford to have such a dilution occur.
Despite this, it would generally be desirable to provide microfluidic systems, methods of using these systems and methods of designing these systems, which systems are capable of maximizing throughput by permitting materials to be introduced serially, with a minimum amount of space between them. The present invention meets these and a variety of other needs.
The present invention generally provides methods, devices and systems having optimized throughput rates for serially processed materials in microfluidic channel systems.
For example, in a first aspect, the present invention provides methods of serially transporting a plurality of test compound plugs in a microfluidic channel. The method comprises providing a first microfluidic channel having a smallest cross sectional dimension that is less than a maximum dimension d, where:       d    =                  P        n            ⁢                        D                      2            ⁢            KT                                ;
A first test compound plug is introduced, followed by an adjacent spacer fluid plug, where P is the period of time used to introduce the test compound plug and the adjacent spacer fluid plug into the channel. D is the diffusion coefficient of the test compound in the test compound plug. T is an amount of time for the test compound plug to move from introduction into the channel to a point of detection. K is a proportionality constant based upon the nature of the channel""s cross sectional shape. n is a ratio of initial plug length to average dispersion distance for the test compound in the test compound plug in time T, provided that T is greater than P. A second test compound plug is then introduced adjacent to the spacer fluid plug.
Another aspect of the present invention is a microfluidic device, comprising a body structure which has at least a first microfluidic channel disposed within it. The channel has a smallest cross-sectional dimension of less than d, wherein:   d  =                              L          p                n            -                        2          ⁢          DT                            U      ⁢                                    2            ⁢            KT                    D                    
First and second test compound plugs are disposed in the channel separated by a spacer fluid plug. The first test compound plug and spacer fluid plug have a length of Lp, n is a ratio of initial plug length to desired dispersion distance of the test compound in the test compound plug, and is between about 0.5 and about 10, D is a diffusion coefficient of the first test compound. T is an amount of time for the test compound plug to move from introduction into the channel to a point of detection. U is an average linear velocity of the test compound plug through the first microscale channel. K is the proportionality constant based upon the nature of the channel""s cross-sectional shape.
A further aspect of the present invention is a method of designing a microfluidic channel network for performing a serial analysis. The method comprises selecting a cycle length of a test plug containing a test compound plug and a spacer plug. A diffusion coefficient of the test compound is identified. A total reaction time is selected for the test compound. One or more of a maximum channel diameter and a channel length for carrying out the analysis is determined, based upon the cycle length, diffusion coefficient and total reaction time. The test compound in the test compound plug disperses across less than 50% of the spacer fluid plug during the total reaction time.